scholarly journals Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

2021 ◽  
Author(s):  
Sylvan C Baca ◽  
Cassandra Singler ◽  
Soumya Zacharia ◽  
Ji-Heui Seo ◽  
Tunc Morova ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Steady State ◽  
Binding Sites ◽  
Association Studies ◽  
Prostate Cancer Risk ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Context Dependent

Methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs), are widely used to functionally annotate trait-associated variants, but they are limited in identifying context-dependent effects on transcription. To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for nominating variants that impact traits through their effects on chromatin state. CWAS associates the genetic determinants of cistromes (e.g., the genome-wide profiles of transcription factor binding sites or histone modifications) with traits using summary statistics from genome-wide association studies (GWAS). We performed CWASs of prostate cancer and androgen-related traits, using a reference panel of 307 prostate cistromes from 165 individuals. CWAS nominated susceptibility regulatory elements or androgen receptor (AR) binding sites at 52 out of 98 known prostate cancer GWAS loci and implicated an additional 17 novel loci. We functionally validated a subset of our results using CRISPRi and in vitro reporter assays. At 28 of the 52 risk loci, CWAS identified regulatory mechanisms that are not observable via eQTLs, implicating genes with complex or context-specific regulation that are overlooked by current approaches that relying on steady-state transcript measurements. CWAS genes include transcription factors that govern prostate development such as NKX3-1, HOXB13, GATA2, and KLF5. Moreover, CWAS boosts discovery power in modestly sized GWAS, identifying novel genetic associations mediated through AR binding for androgen-related phenotypes, including resistance to prostate cancer therapy. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting context-dependent transcriptional regulation.

scholarly journals Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

2021 ◽  
Author(s):  
Matthew Freedman ◽  
Sylvan Baca ◽  
Cassandra Singler ◽  
Soumya Zacharia ◽  
Ji-Heui Seo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Steady State ◽  
Binding Sites ◽  
Association Studies ◽  
Prostate Cancer Risk ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Context Dependent

Abstract Methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs), are widely used to functionally annotate trait-associated variants, but they are limited in identifying context-dependent effects on transcription. To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for nominating variants that impact traits through their effects on chromatin state. CWAS associates the genetic determinants of cistromes (e.g., the genome-wide profiles of transcription factor binding sites or histone modifications) with traits using summary statistics from genome-wide association studies (GWAS). We performed CWASs of prostate cancer and androgen-related traits, using a reference panel of 307 prostate cistromes from 165 individuals. CWAS nominated susceptibility regulatory elements or androgen receptor (AR) binding sites at 52 out of 98 known prostate cancer GWAS loci and implicated an additional 17 novel loci. We functionally validated a subset of our results using CRISPRi and in vitro reporter assays. At 28 of the 52 risk loci, CWAS identified regulatory mechanisms that are not observable via eQTLs, implicating genes with complex or context-specific regulation that are overlooked by current approaches that relying on steady-state transcript measurements. CWAS genes include transcription factors that govern prostate development such as NKX3-1, HOXB13, GATA2, and KLF5. Moreover, CWAS boosts discovery power in modestly sized GWAS, identifying novel genetic associations mediated through AR binding for androgen-related phenotypes, including resistance to prostate cancer therapy. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting context-dependent transcriptional regulation.

Venous thromboembolism and prostate cancer: what about genetic markers?

2021 ◽  
Vol 22 (6) ◽  
pp. 365-373
Author(s):  
Sofia Coelho Abreu ◽  
Valéria Tavares ◽  
Filipa Carneiro ◽  
Rui Medeiros
Keyword(s):  
Prostate Cancer ◽  
Venous Thromboembolism ◽  
Genetic Markers ◽  
Association Studies ◽  
Genome Wide Association ◽  
Clinical Implications ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Genome Wide ◽  
The Relationship

Aim & methods: To review the existing literature concerning the relationship between venous thromboembolism (VTE) and prostate cancer (PC) and explore the putative biological and clinical implications of VTE genetic markers on PC patients by screening the PubMed database. Results: Considering the roles of VTE genome-wide association studies-identified genetic determinants in disease development in the general population, these variants might also underlie the susceptibility for PC-related VTE. Therefore, they could help to identify those with a positive benefit-to-harm ratio for thromboprophylaxis approaches during cancer therapy management, thereby improving patient’s prognosis. Conclusion: Future studies are mandatory to explore the relationship between VTE and PC and dissect the predictive value of VTE genome-wide association studies-identified genetic determinants in PC patients, given their clinical implications.

scholarly journals Post genome-wide association studies functional characterization of prostate cancer risk loci

BMC Genomics ◽  
2013 ◽  
Vol 14 (Suppl 8) ◽  
pp. S9 ◽  
Author(s):  
Junfeng Jiang ◽  
Weirong Cui ◽  
Wanwipa Vongsangnak ◽  
Guang Hu ◽  
Bairong Shen
Keyword(s):  
Prostate Cancer ◽  
Cancer Risk ◽  
Association Studies ◽  
Functional Characterization ◽  
Prostate Cancer Risk ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Allele-specific epigenetic activity in prostate cancer and normal prostate tissue implicates prostate cancer risk mechanisms

2021 ◽  
Author(s):  
Anamay Shetty ◽  
Ji-Heui Seo ◽  
Connor A Bell ◽  
Edward P O'Connor ◽  
Mark Pomerantz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Risk ◽  
Association Studies ◽  
Significant Risk ◽  
Prostate Cancer Risk ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Normal Prostate ◽  
Allele Specificity ◽  
Specific Regulation

Background: Genome-wide association studies of prostate cancer have identified >250 significant risk loci, but the causal variants and mechanisms for these loci remain largely unknown. Here, we sought to identify and characterize risk harboring regulatory elements by integrating epigenomes from primary prostate tumor and normal tissues of 27 patients across the H3K27ac, H3K4me3, and H3K4me2 histone marks and FOXA1 and HOXB13 transcription factors. Results: We identified 7,371 peaks with significant allele-specificity (asQTL peaks). Showcasing their relevance to prostate cancer risk, H3K27ac T-asQTL peaks were the single annotation most enriched for prostate cancer GWAS heritability (40x), significantly higher than corresponding non-asQTL H3K27ac peaks (14x) or coding regions (14x). Surprisingly, fine-mapped GWAS risk variants were most significantly enriched for asQTL peaks observed in tumors, including asQTL peaks that were differentially imbalanced with respect to tumor-normal states. These data pinpointed putative causal regulatory elements at 20 GWAS loci, of which 11 were detected only in the tumor samples. More broadly, tumor-specific asQTLs were enriched for expression QTLs in benign tissues as well as accessible regions found in stem cells, supporting a hypothesis where some germline variants become reactivated during/after transformation and can be captured by epigenomic profiling of the tumor. Conclusion: Our study demonstrates the power of allele-specificity in chromatin signals to uncover GWAS mechanisms, highlights the relevance of tumor-specific regulation in the context of cancer risk, and prioritizes multiple loci for experimental follow-up.

scholarly journals Assessment of possible association between rs378854 and prostate cancer risk in the Serbian population

2013 ◽  
Vol 65 (2) ◽  
pp. 475-486
Author(s):  
G. Brajuskovic ◽  
Zorana Nikolic ◽  
A. Kojic ◽  
Dusanka Savic-Pavicevic ◽  
Snezana Cerovic ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Association Studies ◽  
Prostate Cancer Risk ◽  
Quality Analysis ◽  
Control Group ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Study Population ◽  
Hardy Weinberg Equilibrium

Prostate cancer (PCa) is the second most commonly diagnosed cancer among men worldwide. Despite its high incidence rate, the molecular basis of PCa onset and its progression remains little understood. Genome-wide association studies (GWAS) have greatly contributed to the identification of single nucleotide polymorphisms (SNP) associated with PCa risk. Several GWAS identified 8q24 as one of the most significant PCa-associated regions. The aim of this study was to evaluate the association of SNP rs378854 at 8q24 with PCa risk in the Serbian population. The study population included 261 individuals diagnosed with PCa, 257 individuals diagnosed with benign prostatic hyperplasia (BPH) and 106 healthy controls. Data quality analysis yielded results showing deviations from Hardy-Weinberg equilibrium in groups of PCa patients and BPH patients as well as in the control group. There was no significant association between alleles and genotypes of the genetic variant rs378854 and PCa risk in the Serbian population.

scholarly journals Large-scale transcriptome-wide association study identifies new prostate cancer risk regions

2018 ◽  
Author(s):  
Nicholas Mancuso ◽  
Simon Gayther ◽  
Alexander Gusev ◽  
Wei Zheng ◽  
Kathryn L. Penney ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Association Study ◽  
Large Scale ◽  
Association Studies ◽  
Probabilistic Approach ◽  
Prostate Cancer Risk ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Causal Genes ◽  
Credible Set

AbstractAlthough genome-wide association studies (GWAS) for prostate cancer (PrCa) have identified more than 100 risk regions, most of the risk genes at these regions remain largely unknown. Here, we integrate the largest PrCa GWAS (N=142,392) with gene expression measured in 45 tissues (N=4,458), including normal and tumor prostate, to perform a multi-tissue transcriptomewide association study (TWAS) for PrCa. We identify 235 genes at 87 independent 1Mb regions associated with PrCa risk, 9 of which are regions with no genome-wide significant SNP within 2Mb. 24 genes are significant in TWAS only for alternative splicing models in prostate tumor thus supporting the hypothesis of splicing driving risk for continued oncogenesis. Finally, we use a Bayesian probabilistic approach to estimate credible sets of genes containing the causal gene at pre-defined level; this reduced the list of 235 associations to 120 genes in the 90% credible set. Overall, our findings highlight the power of integrating expression with PrCa GWAS to identify novel risk loci and prioritize putative causal genes at known risk loci.

scholarly journals Transcriptional Regulation of RUNX1: An Informatics Analysis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1175
Author(s):  
Amarni L. Thomas ◽  
Judith Marsman ◽  
Jisha Antony ◽  
William Schierding ◽  
Justin M. O’Sullivan ◽  
...  
Keyword(s):  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Runx1 Gene ◽  
Gene Regulatory Elements ◽  
Important Regulator ◽  
Aml1 Gene ◽  
Regulatory Landscape

The RUNX1/AML1 gene encodes a developmental transcription factor that is an important regulator of haematopoiesis in vertebrates. Genetic disruptions to the RUNX1 gene are frequently associated with acute myeloid leukaemia. Gene regulatory elements (REs), such as enhancers located in non-coding DNA, are likely to be important for Runx1 transcription. Non-coding elements that modulate Runx1 expression have been investigated over several decades, but how and when these REs function remains poorly understood. Here we used bioinformatic methods and functional data to characterise the regulatory landscape of vertebrate Runx1. We identified REs that are conserved between human and mouse, many of which produce enhancer RNAs in diverse tissues. Genome-wide association studies detected single nucleotide polymorphisms in REs, some of which correlate with gene expression quantitative trait loci in tissues in which the RE is active. Our analyses also suggest that REs can be variant in haematological malignancies. In summary, our analysis identifies features of the RUNX1 regulatory landscape that are likely to be important for the regulation of this gene in normal and malignant haematopoiesis.

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